A Nationwide Central Diagnosis for Pediatric CNS Tumors in Japan: The JCCG Brain Tumor and Pathology Committees

In 2016, the Japan Children's Cancer Group launched a nationwide research initiative to provide central diagnosis incorporating pathology review and molecular profiling for pediatric central nervous system (CNS) tumors. Over the first eight years, 2224 cases were registered. Non–next-generation sequencing analyzes, such as pyrosequencing and NanoString, were routinely performed, mainly for glioma, medulloblastoma, and ependymoma. Additional analyzes, including methylation profiling and RNA sequencing, were conducted for selected diagnostically challenging cases. The most common diagnoses were low-grade glioma (26%), medulloblastoma (18%), germ cell tumor (16%), high-grade glioma (12%), and ependymoma (11%). Diagnostic or targetable alterations were detected in nearly half of the glioma samples. Among medulloblastomas, Group 4 was the most prevalent subgroup (48%), followed by SHH-activated (28%), Group 3 (14%), and WNT-activated (11%). Among ependymomas, 95% of posterior fossa ependymomas were classified as PFA, and 72% of supratentorial ependymomas were positive for ZFTA fusion. Methylation-based classification enabled diagnostic refinement and identification of recently recognized novel subtypes. The integration of histopathological review by central pathologists and detailed molecular analyzes facilitated the recognition of rare tumors not yet defined in the World Health Organization classification. Our experience underscores the value of integrated diagnosis, which is now regarded as standard practice for pediatric CNS tumors, and highlights the urgent need for a sustainable clinical framework that incorporates molecular testing. This report represents the first comprehensive overview of the pediatric CNS tumor landscape in Japan in the molecular era.